Blood coagulation timer

ABSTRACT

The clotting time of blood is determined at the instant of the initiation of clotting by detecting the sharp change in electrical resistance of a resistive circuit component having a large negative or positive temperature coefficient of resistance, immersed in the blood. The clotting time may be indicated visually, or audibly, or a time-temperature reading may be continuously recorded on a strip chart or the like or a combination of such indicators may be used.

United States Patent [191 Bostick et al.

[111 3,821,643 June 28, 1974 1 BLOOD COAGULATION TIMER [75] Inventors:William Derry Bostick; Peter William Carr, both of Athens. Ga.

[73] Assignee: Research Corporation, New York,

221 Filed: May 29,1973 21 Appl. No.: 364,278

[52] US. Cl. 324/65 R, 23/230 B, 73/15 A, 73/64.1, 128/2 G [51] Int. ClG01r 27/02 [58] Field of Search..' 324/65R, 30 B, 65 D; 128/2 G, 2.1 R,2.1 E, 2 E; 23/230 B; 73/15 A, 64.1, 322 AR [56] References Cited UNITEDSTATES PATENTS 3,267,362 8/1966 Page 128/2G 3,268,804 8/1966 Young 128/2G 3,553,481 1/1971 Hasenbeck 324/65 R X 3,699,437 10/1972 Ur 324/65 RPrimary Examiner-Stanley T. Krawczewicz Attorney, Agent, orFirm-Cameron, Kerkham, Sutton, Stowell & Stowell [57 ABSTRACT Theclotting time of blood is determined at the instant of the initiation ofclotting by detecting the sharp change in electrical resistance of aresistive circuit component having a large negative or positivetemperature coefficient of resistance, immersed in the blood. Theclotting time may be indicated visually, or audibly, or atime-temperature reading may be continuously recorded on a strip chartor the like or a combination of such indicators may be used.

4 Claims, 4 Drawing Figures mmmm 1m 3321.843

SHHY l M 2 TO THERMISTOR v 38a 38b 4 I w Q vey states that over500,000,000 hematological tests BLQQD COAGULATION T ER atheiiiiistotjiii atis mouiitiag aiamana er r6 stailatory motion in saidsample holder, and circuit means I for determining an abrupt change inthe resistance of siad thermistor.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

The invention will be more fully described in refer- BACKGROUND OF THEiNVENTiON ence to the accompanying drawing wherein: Blood clotting timeor the time at which fibrinogen, i is Perspective View of a bieedeiettitig time a protein f d i l forms a d bl d or measuring deviceconstructed in accordance with the web is important to hematology inthat clotting time is l 0 teaching of this invention; 7 the measuredvariable in many clinical tests such as: I 2 i an nlarged perspectiveview of a portion of 1. whole blood clotting time 1 the device shown inFIG. 1; 2. clotting time of recalcified plasma FIG. 3 is an electricaldiagram of a portion of the cir- 3. contact activation test cuit for thedevice of the invention; and

4.,(a) thrombin generation test (TGT) (b) Hicks-Pitney modification ofTOT 5. thrombin time for fibrinogen determination 6. thromboplastingeneration test 7. quick one-stage assay for prothrombin 8. prothrombintime test (Link-Shapiro modifica- 15 FIG. 4 is a typical curve-plot ofthe output voltage versus time during a coagulation time determinatiomReferring now to FIGS. 1, 2 and 3, 10 generally de time determinationdevice.

mm) The device 10 in general includes, a constant-temper- Owrenprothrombimprocohvertin test ature bath or block 12; a variable agitatormechanism 10. Ware-Stragnell modification of prothrombin- 14; a m bloodagitator f thermistor Support proconvemn test l6 and timer and controlchassis 18. l 1. prothrombin consumption test The constant temperaturemeans 12 includes control 12. two-stage method for measurement ofprothror means 20 whereby a water bath or metal block within bin thehousing 22 may be maintained at a relatively conl3. screening tests forclotting-factor deficiencies stant temperature of, for example, about 37C.

' 14. partial thromboplastin time A sample holder 24 is received withinthe bath with aetivated P t l oplastin time the opening in the sampleholder being axially aligned 16. differential partial thromboplastintime b l th ib t t t h ftzfi,

H PRIOR R The chuck or coupling 28 mounts the mixing oragitator rod 30to the, vibrator The extended end of the Notwlthstandmg the Importanceof Such tests (a rod 30 mounts a conventional commercial semiconper yearwere run in 1969) and notwithstanding that a number of companies havedeveloped and commercial ized various instruments most do not conformto.the

of resistance, which may be either negative or positive, known in theart as a thermistor.

notes one embodiment of our improved blood clotting ductor bead 32having a large temperature coefficient requirements or have thecharacteristics of an ideal re- The thermistor is e a giass tube and a icording instrument for measurement of blood coagu1a lar plast c or glassdisc 36 is fitted over the thermistor tion which has been defined as onethat will. Continw rod leaving the glass or otherwise enclosedtemperature Ously measure the clotting process, provide an immedpsensitive tip exposed. Internally ofthe glass tube 34 are ate recordedgraph as the Clotting process goes on mounted the pair of electricalconductors 38a and 38b thermostatically controlled with short warm-upperiod, which are connected to the thermistor The mixer or i .be verysensitive and be equally suitable for a variety Vibrator 14 may b ofCommerciai design and include of coagulation studies. Addition ofreaction initiators a Control-knob 40 so that-the Vibratory amplitude ofthe such as CaCl should automatically start the measure device itiayadjusted so that mixing e the ment of time. Multiple simultaneousdeterminations P e is neither too "ioieiit Qt too siuggisi'i' should bepossible and the clotting specimen should not As shown in FIG. 3, theexternal ends of leads 38a i be subjected to any stress. The machineshould require a d 381; are connected to form one leg of a Wheatstone mll amounts of blood, be p q and y I bridge 42. Other legs .of the bridgeinclude resistances dle. With such an instrument clotting tests could beR d R f ab ut 2K!) and the remaining leg has conmore readilystandardized, the s je e error nected thereto a variable resistor suchas resistance de- ;vide an instrument which will meet the mostsignificant m y reduced, a Considerable time Savedin cade box R Thebridge is powered by several 1.5 volt dition, the ideal instrumentshould provide acquisition ll 44 wir d in series, which power supply maybe of additional information not obtainable by other methi bl as h Th tt le d 46 nd 46b may ods and production of permanent rec be connected toa commercial recorder, such as a PRESENT INVENTION Heath recorder 100 mvfull scale, or to a simple volt,-

It is a primary object of the present invention to proof thehereinbefore listed characteristics of an ideal i blood clot timer. n

It isanother object to provide such a device which is 1 THEORY OFOPERATION relatively simple in construction; reliable in use andrelatively' simple to operate. Y The intemal'temperature of thethermistor (T is the I Other objects and advantages are provided by aisum of two factors: the temperature of the thermistors blood clotindicating device comprising a blood sample environment, i.e., thesolution temperature (T and holder, means for maintaining the holder anda blood 1 the temperature difference clue to self-heating (AT) samplecontainable therein at a constant temperature, thusly:

The term, AT, is the ratio of two factors, the power (P) dissipatedbyohmic heating and dissipation constant (8) AT =1} R /5 which is definedin milliwatts C. R,- is the resistance of the thermistor at T and i isthe currentflowing in the thermistor. The dissipation constant dependsupon severalterms including the thermal conductance of the surroundingmedium (A) the velocity flv) of the solution in a thin layer around thethermistor, a proportionality constant (a) which depends upon geometry.and a medium independent term inherent to the thermistor (8 8 6,,aA-flv) Combining these equations we have:

E T T/8n When a clot forms the term a \-f(v) undergoes a very rapiddecrease as sketched in FIG. 4. The change is due to some combination ofa drastic decrease in )t or in the solution velocity. Thechange in 6 isreflected in a rise in'T This rise is registered by the Wheatstonebridge as follows:

1'= 0l +B( 1- 1.)] n (BEAR/R0) EBB 'r The terms B,E,, and R are thetemperature coefficient of resistance, the applied bridge voltage andthe thermistors resistance at T respectively. A R is the change in thethermistors resistance. When T undergoes a rapid change due to thechange in 8, then A R and e,,, the bridge output potential, change inproportion to T Now referring to FIG. 4 of the drawing illustrating atypical voltage-time plot of a device constructed as disclosed herein,point A designates the initiation of clotting reaction and the startingof the timing device by the addition of a thromboplastin to the bloodsample; point B is the extrapolated end point; C is the linear distance(time) between points A and B corresponding to the clotting time. Thedevice has a constant output voltage between points A and A then thevoltage drops upon the addition of, for example, 0.1 ml of 0.1 M CaCl toL0 ml of plasma thereby indicating the start of the timing process. Asthe constant temperature bath brings the temperature up toward thecontrol point A we have a gradual increase in voltage between points Aand B. At point B the resistance change of the thermistor registers asthe sharp change in slope as the clot formation affects the thermaldissipation of heat about the thermistor tip, thus providing a verysensitive, im-

mediate record of clot formation. At point B the timer is read and/orautomatically stopped.

' EXAMPLES test tube (24). The tube is lowered into the thermostatedwater bath which is controlled to i 005 C. A-2KQ thermistor mounted inthe chuck of a vibratory or oscillatory mixer 14 is immersed in thesample. The thermistor is electrically connected to the Wheatstonebridge (42) whose disbalance may be monitored on a strip chart recorder,not shown.

The sample tube is equilibrated with the bath while a bridge outputbaseline is established. A small aliquot micro liters) of().4M calciumchloride is injected from a glass syringe. and the timer issimultaneously started. This is point A in H6. 4 and the sharp voltagedecrease is a result of temperature mismatch and reaction of the addedcalcium chloride solution with the anticoagulant used in samplecollection. At the moment when the sample clots the slope of thevoltage-time curve changes drastically as at point B, FIG. 4.

Table l illustrates the reproducibility of the tests:

From the foregoing description it will be seen that the instrument ofthe invention fully accomplishes the aims and objects herein set forthand others. It will also be recognized by those skilled in the art thatvarious modifications may be made in the form of the illustrated timerwithout departing from the scope of the present invention, for example,the timer may be provided with a series of openings to receive a numberof blood samples and the clot-time measurements may be made sequentiallywith automatic introduction of the proper amounts of thromboplastinsolution.

-We claim:

1. A blood clotting indicating device comprising a blood sample holder,means for maintaining the holder and a blood sample containable thereinat a constant temperature, a resistive circuit component having a largetemperature coefficient of resistance, means 'mounting said resistivecircuit component for movement in said sample holder, and circuit meansfor determining an abrupt change in the resistance of said resistivecircuit component.

2. The invention defined in claim 1 wherein the resistive circuitcomponent comprises a thermistor.

3. The invention defined in claim 1 wherein said resistive circuitcomponent has a large negative temperature coefficient of resistance.

4. The invention defined in claim 1 wherein said resistive circuitcomponent has a large positive temperature coefficient of resistance.

1. A blood clotting indicating device comprising a blood sample holder,means for maintaining the holder and a blood sample containable thereinat a constant temperature, a resistive circuit component having a largetemperature coefficient of resistance, means mounting said resistivecircuit component for movement in said sample holder, and circuit meansfor determining an abrupt change in the resistance of said resistivecircuit component.
 2. The invention defined in claim 1 wherein theresistive circuit component comprises a thermistor.
 3. The inventiondefined in claim 1 wherein said resistive circuit component has a largenegative temperature coefficient of resistance.
 4. The invention definedin claim 1 wherein said resistive circuit component has a large positivetemperature coefficient of resistance.